Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-03-19
2001-06-12
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06245813
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to the use of Ubenimex or the salt thereof and pharmaceutical composition comprising Ubenimex or the salt thereof for the treatment of viral Hepatitis.
BACKGROUND OF THE INVENTION
Viral Hepatitis is a worldwide infectious disease with great hazard to human health, and at least five pathogens of hepatitis virus have been found, i.e, HAV, HBV, HCV, HDV and HEV respectively. All of the 5 viruses can induce acute Hepatitis, which can progress to chronic hepatitis in the case of HBV, HCV and HDV infection. Acute Hepatitis has self-limited chracteristic and the patients with acute hepatitis can be healed completely, whereas the treatment of chronic Hapatitis is very difficult, in particular hepatitis B with high disease incidence. At present, over 280 million people are HBeAg carriers, among whom about 78 million suffer from Hepatitis B.
The following are current clinical agents mainly useful in the treatment chronic Hepatitis B.
1. anti-viral agents such as Interferon
Interferon is a relatively ideal anti-chronic Hepatitis B agent at present, and remission occurs in 30~45% of the IFN-treated patients, with HBeAg undetectable and the liver histologically improved. And 5~25% of the patients can be cured, negative for both HBeAg and HBsAg. However, incapable for oral administration and with comparatively high cost, INF therapy is not likely to be widely used, particularly among the non-hospitalized patients. Moreover, patients treated with Interferon are usually associated with sever side effects such as high fever, shivering, hypotention, nausea, diarrhea, myalgia, headache and lassitude. All these factors consist of great barrier for extensive use of INF.
2. other anti-viral agents such as Vidarabine, Vidarabine phosphate, Aciclovir, Forscarnet, Zidovudine, Suramin, Polycytidylic Acid, 2′, 3′-dideoxyl cytidine.
Due to indefinite clinical efficacy and sever side effects, these agents are not put into general use.
3. Immunomodulant
(1) Cytokines such as Thymosine, immune RNA, Transferfactors and Interleukin-2
(2) Hormone such as Adrenocortical hormone and Prostaglandin
(3) Specific and non-specific antigen or specific antibody such as HB vaccine, BCG vaccine, Polysacchride from Mycobacterium graminis, and high potency Immunoglobulin
(4) Compound effecting intercellular cyclic nucleotide such as imidazole agents.
However, these Immunomodulants are still studied in the stage of experimental research.
4. Chinese traditional medicine such as Polyporus umbellatus polysaccharose, aqueous injection with active ingredient from the root of subprostrate sophora, Matrine in injection form and Polylentinan whose herapeutic efficacy, however, remains to be furtherly verified.
Therefore, it is necessary for developping novel anti-viral Hepatitis agents with high efficacy, lower side effect and convenient administration.
DESCRIPTION OF THE INVENTION
This invention aims to develop an anti-viral Hepatitis agent with high efficacy and lower side effects.
After extensive and profound research, the inventor has unexpectedly found that Ubenimex and the salt thereof exhibits good efficacy against Hepatitis, particularly against chronic Hepatitis B, with significantly lower side effect. The present invention is finished on the basis of the above finding.
Ubenimex is a compound of the following formula,
with the chemical name of N-[(2 S, 3 R)-3-amino-2-hydroxyl-4-phenyl butyryl]-Leucine. Firstly isolated from fermentation broth of Streptomyces olivoreticuli (Strain MD
976
- C
7
) by H. Umezawa, the compound demonstred siguificant inhibitory activity against aminopeptidase B and leucine aminopeptidase. [J. Antibiotics, 29, 97-99 (1976)].
In the present, Ubenimex is mainly used as anticancer agent (Jpn. JP 60-9487, Kokai Tokkyo Koho JP 4-193827), agent for relief of radiation side effects. Jpn. Kokai Tokkyo Kohl JP 3-110150), anti-thrombosis agent (Jpu. Kokai Tokky Koho JP 62-72613) and analgesic agent for nervous periphery (U.S. Pat. No. 4,308,256). However, no report has been found to involve its usage in viral Hepatitis treatment.
The present invention firstly relates to the use of Ubenimex and the salt thereof for the treatment of viral Hepatitis, especially for the treatment of chronic Hepatitis B, wherein the effective therapeutic amount of Ubenimex and the salt thereof is administered to the patient with viral Hepatitis, especially with chronic Hepatitis B.
Furthernore, the present invention relates to the use of the pharmaceutical composition comprising Ubenimex or the salt thereof for the treatment of patient with viral Hepatitis, particularly with chronic Hepatitis B, wherein the pharmaceutical composition comprise Ubenimex or the salt thereof, and the pharmaceutically acceptable adjuvant and excipient, with or without other anti-viral Hepatitis agents.
The present invention also relates to the use of Ubenimex or the salt thereof for the manufacture of anti-viral Hepatitis agent, which consist of the effective therapeutic amount of Ubenimex or the salt thereof, and pharmaceutically acceptable adjuvant and excipient, with or without other ant-viral Hepatitis agent.
According to the present invention, Ubenimex and the pharmaceutical composition comprising Ubenimex can be administered by various appropriate route, among which oral administration is preferred. The dosage for administration, depending on the age, sex, and weight of patient, degree of the liver infection, and administration route etc, is usually 10-100 mg per day.
The following examples of pharmacological study are given to illustrate the biological activity of Ubenimex against virul Hepatitis.
REFERENCES:
patent: 4308256 (1981-12-01), McGregor
patent: 2528984 (1976-06-01), None
patent: 60-9487 (1985-03-01), None
patent: 62-72613 (1987-04-01), None
patent: 4-193827 (1992-07-01), None
Hahm et al, NS3-4A of Hepatitis C Virus is a Chymotrypsin-Like Protease, Journal of Virology, vol. 69(4), pp. 2534-2539, 1995.
Ai Lin
Peng Mingxiu
Wang Ping
Ye Chuanhua
Zhou Shanxue
Alston & Bird LLP
Sichuan Industrial Institute of Antibiotics
Travers Russell
LandOfFree
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